Targeting cellular senescence to extend human healthspan at old age and to counteract therapy resistance in late stage cancer. That’s our mission.

Peter de Keizer – Founder Cleara Biotech B.V.

Cleara Biotech

Senescent cells that accumulate in our bodies are a major cause of health problems and enable cancer development as we age. Researchers at Cleara discovered the mechanism how senescent cells escape the natural elimination process. Based on this discovery, Cleara has succesfully developed and optimized therapeutics to treat patients with a range of diseases caused by this failure to clear senescent cells.

FOXO4 induces senescence in stressed cancer cells

FOXO4 can physically interact with p53 under conditions of stress. In response to excessive stress signaling, pathways are turned on to counter the negative consequences. FOXO4-p53 signaling is important for this reponse.

FOXO4 inhibition induces apoptosis in senescent cells via p53

FOXO proteins are downstream targets of the senescence response. Oncogene-mutation, as well as other forms of persistent stress can lead to a chronic damage response. As a consequence, anti-stress signaling is activated. This is for instance evident from FOXO4 phosphorylation and activation. This lead us to the following model (e.g. P.L.J. de Keizer, Ph.D. dissertation and de Keizer et al., 2010, Cancer Research):

First generation of FOXO4-p53 blocking peptides

Identification by our team that FOXO4 is a pivot in maintaining the viability of senescent cells. Using primary senescent cells, we observed that removing FOXO4 could trigger a “clean” cell death response, known as apoptosis. This created a new window of opportunity to eliminate these deleterious cells. As we found FOXO4 to also exert a protective response to chemotherapy, it additionally opened the door towards development of methods to overcome therapy resistance of cancer cells.

Second generation peptide shows efficacy against senescent cells

Generation of the first and second generation of compounds to eliminate senescent and therapy-resistant cancer cells (e.g. patent US20130288981 A1; 2012). Here, we showed for the first time that not only inhibition of FOXO4 itself, but more specifically, blocking the FOXO4-p53 binding by cell-penetrating peptides could effectively eliminate senescent cells and therapy-resistant cancer cells.

Tumors are also sensitive to FOXO4 inhibition

Development of the third generation of FOXO4-based anti-senescence drugs: the FOXO4-DRI peptide, aka Proxofim. This proved to be effective in counteracting signs of chemotoxicity and, excitingly, was able to restore healthspan in models for fast and natural aging, e.g. fur density, behavior and renal function. (Baar et al., Cell, 2017). This research received worldwide media attention, including coverage in numerous TV and radio shows, newspapers and blogs.

Founding of Cleara to continue our evolution of FOXO4-based anti-senescence drugs and generate the fourth generation capable of human translation. Since the selectivity of the third generation compound, FOXO4-DRI, for senescent cells is ~10-fold, it is unfortunately still too dangerous to allow for clinical trials. At Cleara Biotech, it is our mission to improve the safety profile and potency of Proxofim and to do so, we launched the iPROX program to generate “Improved Proxofim”. We are passionate in translating iPROX to humans and combat senescence-driven age-related diseases, including therapy resistant cancer.

Investigation of biomarkers

Every cell in our body has the potential to become senescent as a consequence of various stresses. By unraveling the enormous heterogeneity of senescent cells, our researchers at Cleara identified the genes at the core of the senescence program. In addition, we obtained evidence for the existence of senescence “subtypes” which play different roles in disease development. Based on these discoveries, Cleara is developing new senescence biomarkers for diagnostics and drug targeting.

Cleara, the company

At Cleara Biotech, we are highly motivated to develop safe and effective treatments to counter the negative aspects of aging and target diseases like therapy-resistant late stage cancer. We aim to do so by generating compounds that are capable of selectively eliminating senescent and senescent-like cancer cells. Cleara Biotech is the exciting result of a long and proven academic history of the key members of our scientific team.